Stem cells which are potentially useful for regenerative medicine are now widely studied. Representative stem cells which have been reported include mesenchymal stem cells, neural stem cells, hematopoietic stem cells and pancreatic stem cells.
Mesenchymal stem cells were separated from human adult bone marrow fluid (Pittenger, M. F. et al., Science 284, 143 (1999)). These cells are capable of being differentiated to fat cells, cartilage cells, and bone cells in vitro. As for neural stem cells (Gage, P. H., science 287, 1433-1438 (2000)), separation of neural stem cells from adult central nerve system was first reported in 1992, and separation of stem cells capable of being differentiated to nerve cells, which are originated from adult dermis, was reported (Toma, J. G. et al., Nature Cell Biology, 3, 778-784 (2001)).
Although a number of studies on hematopoietic stem cells have been made, reports on their differentiation functions are relatively new. In 1999, Petersen et al. showed that bone marrow cells are differentiated to hepatic cells (Petersen B. E. et al., Science 284, 1168 (1999)), and in the next year, the fractionated cells obtained by sorting murine hematopoietic cells by c-kithigh, Thy-1low, Linneg and Sca-1+ are transdifferentiated to stem cells (Lagasse, E. et al., Nature Medicine 6, 1229-1234 (2000)). It is thought that hematopoietic stem cells have transdifferentiation abilities, and differentiation thereof to cardiac muscle (Orlic, D. et al., Nature 410, 701-705 (2001)), as well as to alveolar epithelium, intestine epithelium and skin (Orlic, D. et al., supra), has been reported.
Thus, although studies on the mesenchymal or ectodermal stem cells have been progressed, the number of reports on endodermal stem cells is small. As for human hepatic stem cells, although the existence thereof is thought to be indisputable, there are no reports so far which confirmed the stem cells. As for pancreas, the group of Cornelius et al. separated islet-producing stem cells (IPSCs) from an adult mouse, and reported transplantation experiment of the islet prepared from IPSCs in vitro (Ramiya, V. K. et al., Nature Medicine 6, 278-282 (2000)). Although differentiation of these cells into α, β and δ cells was confirmed, differentiation potential to other cells has not been confirmed. Although it has been reported that the stem cells separated by collection of nestin-positive cells from islet differentiated to cells having a phenotype of endocrine or exocrine of pancreas, and to cells having a phenotype of liver (Zulewski, H. et al., Diabetes 50, 521-533 (2001), immunohistological search by using differentiation markers is not shown.
Induction to hepatic or pancreatic cells from ES cells (embryonic stem cells) has been tried, and differentiation to α or β cells of pancreas can be induced (Lumelsky, N, et al., Science 292, 1389-1394 (2001)). However, induction to human hepatic cells has not been reported.